A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease
Shadrin, A. A.; Mucha, S.; Ellinghaus, D.; Makarious, M. B.; Blauwendraat, C.; Sreelatha, A. A.; Heras-Garvin, A.; Ding, J.; Hammer, M.; Foubert-Samier, A.; Meissner, W. G.; Rascol, O.; Pavy-Le Traon, A.; Frei, O. A.; O'Connell, K. S.; Bahrami, S.; Schreiber, S.; Lieb, W.; Müller-Nuraysid, M.; Arnold, A.; Homuth, G.; Schmidt, C. O.; Nöthen, M. M.; Hoffmann, P.; Gieger, C.; European Multiple System Atrophy Study Group, ; Gibbs, J. R.; Franke, A.; Hardy, J.; Wenning, G.; Stefanova, N.; Gasser, T.; Singleton, A.; Houlden, H.; Scholz, S. W.; Andreassen, O. A.; Sharma, M.
Show abstract
We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.
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